Crystalline forms of venlafaxine hydrochloride

ABSTRACT

Crystalline forms of Venlafaxine hydrochloride were found, referred to hereinafter as polymorphic Forms A, B and D. Furthermore, the present invention is directed to processes for the preparation of these crystalline forms and pharmaceutical compositions comprising the crystalline forms.

This application is a 371 of PCT/EP01/12240, filed Oct. 23, 2001.

The present invention is directed to crystalline forms of Venlafaxinehydrochloride, processes for their preparation and pharmaceuticalcompositions comprising these crystalline forms.

The present invention relates to crystalline forms of Venlafaxinehydrochloride. Venlafaxine hydrochloride is known by the chemical name1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanolhydrochloride. Venlafaxine hydrochloride has the following formula:

Venlafaxine is an anti-depressant and acts by inhibiting synaptosomaluptake of norepinephrine (3H-NE) and serotonin (14C-5HT). Processes forthe preparation of Venlafaxine hydrochloride are described inEP-A-112,669 and in Yardley et al., J. Med. Chem., 1990, vol. 33, page2899. This hydrochloride salt is desirable since it enables Venlafaxineto be conveniently formulated. There is still a need to produceVenlafaxine in a reproducible, pure and crystalline form to enableformulations to meet exacting pharmaceutical requirements andspecifications. Furthermore, it is economically desirable that theproduct is stable for extended periods of time without the need forspecialised storage conditions. The processes in the above mentionedpatent and publication result in the preparation of a crystalline formof Venlafaxine hydrochloride having a melting point between 215 and 217°C. which is herein designated as Form C. Surprisingly, there have nowbeen found several novel crystalline forms of Venlafaxine hydrochloride,herein designated as Form A and B, and a new crystalline hydrate ofVenlafaxine hydrochloride, herein designated as Form D. The novel formsof the present invention have a good thermal stability and/or goodsolubility characterisitics. An additional advantage of Form B is thatthis form is thermodynamically more stable than the previous known FormC.

Accordingly, the present invention is directed to the followingpolymorphic Forms A, B and D of Venlafaxine hydrochloride:

A crystalline polymorph of1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloridewhich exhibits a characteristic X-ray powder diffraction pattern withcharacteristic peaks expressed in d-values (Å) at

15.3 (vw), 11.9 (w), 9.6 (w), 9.1 (vw), 8.1 (vw), 7.7 (w), 6.3 (vw), 6.0(m), 5.92 (m) 5.55 (m), 5.46 (vw), 5.20 (m), 5.00 (w), 4.91 (vw), 4.77(m), 4.57 (s), 4.49 (s), 4.31 (s), 4.26 (s), 4.04 (vw), 3.98 (vw), 3.90(vw), 3.82 (w), 3.68 (vw), 3.60 (w), 3.52 (w), 3.45 (vw), 3.33 (m), 3.29(m), 3.22 (vw), 3.15 (vw), 3.07 (vw), 2.87 (vw), 2.81 (w), 2.72 (vw),2.58 (vw), 2.51 (vw), 2.49 (vw), 2.43 (vw), 2.35 (vw);herein designated as Form A. Here and in the following the abbreviationsin brackets mean: (vs)=very strong intensity; (s)=strong intensity;(m)=medium intensity; (w)=weak intensity; (vw)=very weak intensity; and(sh)=shoulder.

A crystalline polymorph of1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloridewhich has characteristic Raman bands, expressed in wave number (cm⁻¹):

3075 (m), 3059 (m), 3014 (s), 3000 (m), 2938 (vs), 2915 (s), 2900 (sh),2863 (m), 2835 (m), 1613 (s), 1583 (w), 1464 (m), 1447 (m), 1273 (m),1238 (m), 1201 (s), 1181 (s), 1142 (m), 1084 (w), 1062 (w), 1045 (m),984 (m), 974 (m), 961 (w), 863 (m), 849 (s), 839 (s), 818 (s), 739 (m),722 (m), 662 (w), 636 (m), 498 (w), 454 (w), 417 (m), 372 (w), 221 (m);herein designated as Form A.

A crystalline polymorph of1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloridewhich exhibits a characteristic X-ray powder diffraction pattern withcharacteristic peaks expressed in d-values (Å) at

13.0 (w), 8.6 (s), 6.5 (m), 5.86 (w), 5.71 (s), 5.34 (vw), 5.22 (vw),5.11 (vw), 4.85 (m), 4.48 (m), 4.36 (vs), 4.08 (s), 3.90 (m), 3.70 (vw),3.50 (vw), 3.47 (w), 3.35 (vw), 3.27 (w), 3.23 (vw), 3.16 (w), 3.10(vw), 3.04 (vw), 3.00 (vw), 2.86 (w), 2.83 (vw), 2.76 (vw), 2.73 (vw),2.71 (vw), 2.62 (vw), 2.55 (m), 2.48 (vw), 2.43 (vw), 2.39 (vw), 2.34(vw);herein designated as Form B.

A crystalline polymorph of1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloridewhich exhibits a characteristic X-ray powder diffraction pattern withcharacteristic peaks expressed in d-values (Å) at

11.7 (s), 10.2 (w), 7.7 (vw), 6.8 (m), 5.90 (vs), 5.67 (w), 5.57 (vw),5.37 (m), 5.04 (w), 4.91 (vw), 4.76 (m), 4.70 (m), 4.53 (w), 4.47 (w),4.42 (vw), 4.32 (m), 4.14 (m), 4.10 (w), 3.95 (vw), 3.84 (w), 3.77 (vw),3.68 (w), 3.60 (vw), 3.50 (w), 3.35 (m), 3.28 (w), 3.15 (w), 3.07 (vw),3.04 (vw), 3.01 (vw), 2.93 (w), 2.84 (w), 2.77 (vw), 2.72 (w), 2.68(vw), 2.63 (w), 2.59 (w), 2.46 (vw), 2.37 (vw), 2.35 (vw), 2.31 (vw),2.27 (vw), 2.26 (vw);herein designated as Form D.

A crystalline polymorph of1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloridewhich has characteristic Raman bands, expressed in wave number (cm⁻¹):

3082 (w), 3058 (m), 3022 (m), 2998 (w), 2972 (m), 2953 (s), 2938 (vs),2916 (m), 2899 (m), 2865 (m), 2856 (m), 2835 (m), 1616 (vs), 1584 (w),1472 (m), 1452 (m), 1440 (m), 1322 (w), 1303 (w), 1268 (m), 1254 (w),1241 (w), 1202 (m), 1182 (s), 1143 (w), 1078 (w), 1062 (w), 1044 (w),980 (m), 973 (w), 862 (w), 848 (s), 840 (s), 817 (vs), 738 (w), 723 (w),661 (w), 637 (m), 417 (m), 375 (w), 277 (w), 224 (m), 178 (w);herein designated as Form D.

Known Form C exhibits a characteristic X-ray powder diffraction patternwith characteristic peaks expressed in d-values (Å) at

12.9 (w), 10.5 (w), 8.6 (vw), 6.9 (s), 6.5 (m), 5.66 (w), 5.52 (w), 5.41(m), 5.25 (w), 5.10 (w), 4.67 (s), 4.47 (w), 4.34 (vs), 4.18 (vs), 4.07(m), 3.99 (vw), 3.87 (vw), 3.69 (vw), 3.55 (m), 3.51 (vw), 3.46 (w),3.39 (w), 3.32 (vw), 3.26 (w), 3.12 (m), 3.09 (w), 2.94 (vw), 2.88 (w),2.83 (m), 2.75 (vw), 2.73 (vw), 2.69 (w), 2.64 (m), 2.55 (m), 2.48 (vw),2.46 (vw), 2.43 (vw), 2.38 (w), 2.35 (vw), 2.32 (w), 2.30 (w), 2.26(vw).

A discussion of the theory of X-ray powder diffraction patterns can befound in “X-ray diffraction procedures” by H. P. Klug and L. E.Alexander, J. Wiley, New York (1974).

Furthermore, the present invention is directed to processes for thepreparation of Forms A, B and D. In addition, the present invention isdirected to processes for the preparation of highly pure crystallineForm B. Highly pure Form B is to be understood having a content of thisform of 95% by weight, especially 97.5% by weight and preferably 99% byweight.

Form A can be prepared by heating Form C to a temperature just above itsmelting point (for example 1 to 20° C., especially 1 to 10° C. above itsmelting point) in order to form crystals of Form A.

Form B can be prepared by equilibrating a slurry of polymorphic Form Cin an organic solvent, preferably an alcoholic or ketone solvent,especially isopropanol, and separating Form B. The process can beperformed with or without the addition of seeding crystals. The additionof seeding crystals is preferred.

Alternatively, Form B can be prepared by dissolving Venlafaxinehydrochloride in an organic solvent, preferably isopropanol, at elevatedtemperature (for example 40 to 80° C., especially 50 to 70° C.) andsubsequent cooling. It is preferred to cool to room temperature. Theconcentration of Venlafaxine hydrochloride is for example 5 to 20% byweight, especially 10 to 15% by weight. The cooling rate can vary and isfor example 0.1 to 2° C. per minute, especially 0.1 to 0.5° C. perminute. Preferably, seeding crystals of Form B are added, especiallywithin the metastable zone width, for example at 1 to 10° C., especially1 to 3° C. below the temperature of complete dissolution. The quantityof added seeding crystals is for example 2 to 10% and especially 10% ofthe quantity of Venlafaxine hydrochloride. The seeding crystals arepreferably ground before the addition.

Form D can be prepared by evaporating an aqueous solution of Venlafaxinehydrochloride. Preferably evaporation is carried out at a temperature of10 to 60° C., most preferably at 20 to 40° C., especially at roomtemperature. It is preferred to carry out evaporation in air.

The preparation of crystalline polymorphic Forms A, B and D is usuallycarried out by using Form C as the starting compound.

Form C can, for example, be obtained by preparing a solution ofVenlafaxine hydrochloride in isopropanol at elevated temperature (forexample 40 to 80° C., especially 50 to 70° C.) and subsequent cooling ofthe solution (for example to 0 to 20° C., especially to about 0° C.).Precipitated Form C can then be separated.

Another object of the present invention are pharmaceutical compositionscomprising an effective amount of crystalline polymorphic Form A, B orD, and a pharmaceutically acceptable carrier.

The polymorphic forms may be used as single components or mixtures.

As to pharmaceutical compositions of Venlafaxine hydrochloride it ispreferred that these contain 25-100% by weight, especially 50-100% byweight, of at least one of the novel forms, based on the total amount ofVenlafaxine hydrochloride. Preferably, such an amount of the novelpolymorphic forms of Venlafaxine hydrochloride is 75-100% by weight,especially 90-100% by weight. Highly preferred is an amount of 95-100%by weight.

The following Examples illustrate the invention in more detail.Temperatures are given in degrees Celsius, parts and percentages are byweight, unless otherwise stated.

EXAMPLE 1 Preparation of Polymorphic Form C

100 parts of Venlafaxine hydrochloride are dissolved in 1600 parts ofisopropanol at a temperature of 60° C. and subsequently cooled to atemperature of 0° C. This leads to the precipitation of Form C. X-raypowder diffraction studies show the product to be polymorphic Form C(see FIG. 1).

EXAMPLE 2 Preparation of Polymorphic Form A

Form C of Venlafaxine hydrochloride is heated just above its meltingpoint. Newly formed crystals of Form A start to grow out of this melt.X-ray powder diffraction studies show the product to be polymorphic FormA (see FIG. 2). A Raman spectrum of Form A is given in FIG. 3.

EXAMPLE 3 Preparation of Polymorphic Form B

A slurry of 100 parts of Form C of Venlafaxine hydrochloride in 800parts of isopropanol is equilibrated for 3 days. Subsequent filtrationand drying gives pure Venlafaxine hydrochloride Form B. X-ray powderdiffraction studies show the product to be polymorphic Form B (see FIG.4).

EXAMPLE 4 Preparation of Polymorphic Form D

80 parts of Form C of Venlafaxine hydrochloride are dissolved in 500parts of water. The solution is evaporated in air at room temperature.This gives Venlafaxine hydrochloride Form D. X-ray powder diffractionstudies show the product to be polymorphic Form D (see FIG. 5). A Ramanspectrum of Form D is given in FIG. 6.

EXAMPLE 5 Preparation of Polymorphic Form B

100 parts of Form C of Venlafaxine hydrochloride are dissolved in 800parts of isopropanol at 70° C. At 63° C. 10 parts of ground Form B ofVenlafaxine hydrochloride are added as seeding crystals. The temperatureis lowered with a cooling rate of 0.1° C. per minute to roomtemperature. Subsequent filtration and drying gives pure Venlafaxinehydrochloride Form B.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic X-ray powder diffraction pattern for Form C

FIG. 2 is a characteristic X-ray powder diffraction pattern for Form A

FIG. 3 is a characteristic Raman spectrum of Form A

FIG. 4 is a characteristic X-ray powder diffraction pattern for Form B

FIG. 5 is a characteristic X-ray powder diffraction pattern for Form D

FIG. 6 is a characteristic Raman spectrum of Form D

1. A crystalline polymorph of1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloridewhich exhibits a characteristic X-ray powder diffraction pattern withcharacteristic peaks expressed in d-values (Å) at 15.3 (vw), 11.9 (w),9.6 (w), 9.1 (vw), 8.1 (vw), 7.7 (w), 6.3 (vw), 6.0 (m), 5.92 (m), 5.55(m), 5.46 (vw), 5.20 (m), 5.00 (w), 4.91 (vw), 4.77 (m), 4.57 (s), 4.49(s), 4.31 (s), 4.26 (s), 4.04 (vw), 3.98 (vw), 3.90 (vw), 3.82 (w), 3.68(vw), 3.60 (w), 3.52 (w), 3.45 (vw), 3.33 (m), 3.29 (m), 3.22 (vw), 3.15(vw), 3.07 (vw), 2.87 (vw), 2.81 (w), 2.72 (vw), 2.58 (vw), 2.51 (vw),2.49 (vw), 2.43 (vw), 2.35 (vw); wherein (s)=strong intensity;(m)=medium intensity; (w)=weak intensity; and (vw)=very weak intensity.2. A crystalline polymorph of1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloridewhich has characteristic Raman bands, expressed in wave number (cm⁻¹):3075 (m), 3059 (m), 3014 (s), 3000 (m), 2938 (vs), 2915 (s), 2900 (sh),2863 (m), 2835 (m), 1613 (s), 1583 (w), 1464 (m), 1447 (m), 1273 (m),1238 (m), 1201 (s), 1181 (s), 1142 (m), 1084 (w), 1062 (w), 1045 (m),984 (m), 974 (m), 961 (w), 863 (m), 849 (s), 839 (s), 818 (s), 739 (m),722 (m), 662 (w), 636 (m), 498 (w), 454 (w), 417 (m), 372 (w), 221 (m);wherein (vs)=very strong intensity; (s)=strong intensity; (m)=mediumintensity; (w)=weak intensity; and (sh)=shoulder.
 3. A process for thepreparation of a crystalline polymorph according to claim 1, whichcomprises heating polymorphic Form C to a temperature just above itsmelting point in order to form crystals of the crystalline polymorphaccording to claim
 1. 4. A pharmaceutical composition comprising aneffective amount of a crystalline polymorphic form according to any ofclaim 1, and a pharmaceutically acceptable carrier.